Mechanical Stress Signaling in Pancreatic Cancer Cells Triggers p38 MAPK- and JNK-Dependent Cytoskeleton Remodeling and Promotes Cell Migration via Rac1/cdc42/Myosin II.
Mechanical Stress Signaling in Pancreatic Cancer Cells Triggers p38 MAPK- and JNK-Dependent Cytoskeleton Remodeling and Promotes Cell Migration via Rac1/cdc42/Myosin II.
复制标题
DOI：
10.1158/1541-7786.mcr-21-0266
复制
发表时间：
2022-03-01
期刊：
影响因子：
--
通讯作者：
Zervantonakis IK
中科院分区：
文献类型：
--
作者：
Kalli M;Li R;Mills GB;Stylianopoulos T;Zervantonakis IK
晚期或转移性胰腺癌对现有疗法具有高度耐药性，迫切需要新的治疗方法来改善患者的预后。目前的研究集中在替代治疗方法，目标是胰腺肿瘤的异常微环境和由此产生的肿瘤内部机械应力升高。然而，机械应力调节胰腺癌转移潜力的潜在机制仍然难以捉摸。在此，我们使用蛋白质组学分析来描绘驱动胰腺癌细胞运动的机械应力诱导的信号级联。蛋白质组学分析，以及选择性蛋白质抑制和siRNA治疗，揭示了机械应力通过激活p38 MAPK/HSP 27和JNK/c-Jun信号轴，以及激活肌动蛋白细胞骨架重塑：Rac 1，cdc 42和肌球蛋白II来增强细胞迁移。此外，机械应力上调转录因子与上皮间质转化，刺激应力纤维和丝状伪足的形成。与对照条件相比，p38 MAPK和JNK抑制导致较低的细胞增殖和更有效地阻断机械应力下的细胞迁移。在机械应力下增强的肿瘤细胞运动性被cdc 42和Rac 1沉默有力地降低，而对增殖没有影响。我们的研究结果强调了靶向已经适应肿瘤微环境中机械应力的癌细胞中异常信号传导的重要性，作为有效限制胰腺癌细胞迁移的新方法。我们的研究结果强调，机械应力激活p38 MAPK和JNK信号轴，并通过上调肌动蛋白细胞骨架重塑cdc 42和Rac 1刺激胰腺癌细胞迁移。
Advanced or metastatic pancreatic cancer is highly resistant to existing therapies, and new treatments are urgently needed to improve patient outcomes. Current studies focus on alternative treatment approaches that target the abnormal microenvironment of pancreatic tumors and the resulting elevated mechanical stress in the tumor interior. Nevertheless, the underlying mechanisms by which mechanical stress regulates pancreatic cancer metastatic potential remain elusive. Herein, we used a proteomic assay to profile mechanical stress–induced signaling cascades that drive the motility of pancreatic cancer cells. Proteomic analysis, together with selective protein inhibition and siRNA treatments, revealed that mechanical stress enhances cell migration through activation of the p38 MAPK/HSP27 and JNK/c-Jun signaling axes, and activation of the actin cytoskeleton remodelers: Rac1, cdc42, and myosin II. In addition, mechanical stress upregulated transcription factors associated with epithelial-to-mesenchymal transition and stimulated the formation of stress fibers and filopodia. p38 MAPK and JNK inhibition resulted in lower cell proliferation and more effectively blocked cell migration under mechanical stress compared with control conditions. The enhanced tumor cell motility under mechanical stress was potently reduced by cdc42 and Rac1 silencing with no effects on proliferation. Our results highlight the importance of targeting aberrant signaling in cancer cells that have adapted to mechanical stress in the tumor microenvironment, as a novel approach to effectively limit pancreatic cancer cell migration. Our findings highlight that mechanical stress activated the p38 MAPK and JNK signaling axis and stimulated pancreatic cancer cell migration via upregulation of the actin cytoskeleton remodelers cdc42 and Rac1.